PSTPIP1-LYP phosphatase interaction: structural basis and implications for autoinflammatory disorders

DOI: 10.1007/s00018-022-04173-w

Authors: Jose Antonio Manso (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Tamara Marcos (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Virginia Ruiz-Martín (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Javier Casas (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Pablo Alcon (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Mariano Sánchez Crespo (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Yolanda Bayón (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Jose M. De Pereda (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca) , Andrés Alonso (Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-Universidad de Salamanca)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cellular And Molecular Life Sciences , VOL 79

State: Published (Approved)
Published: February 2022
Diamond Proposal Number(s): 10121

Abstract: Mutations in the adaptor protein PSTPIP1 cause a spectrum of autoinflammatory diseases, including PAPA and PAMI; however, the mechanism underlying these diseases remains unknown. Most of these mutations lie in PSTPIP1 F-BAR domain, which binds to LYP, a protein tyrosine phosphatase associated with arthritis and lupus. To shed light on the mechanism by which these mutations generate autoinflammatory disorders, we solved the structure of the F-BAR domain of PSTPIP1 alone and bound to the C-terminal homology segment of LYP, revealing a novel mechanism of recognition of Pro-rich motifs by proteins in which a single LYP molecule binds to the PSTPIP1 F-BAR dimer. The residues R228, D246, E250, and E257 of PSTPIP1 that are mutated in immunological diseases directly interact with LYP. These findings link the disruption of the PSTPIP1/LYP interaction to these diseases, and support a critical role for LYP phosphatase in their pathogenesis.

Journal Keywords: Immunology; Auto-inflammation; LYP; PSTPIP1

Diamond Keywords: Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA)

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 17/02/2022 08:59

Documents:
Manso2022_Article_PSTPIP1-LYPPhosphataseInteract.pdf

Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)